Abstract
In the cornea, healing of the wounded avascular surface is an intricate process comprising the involvement of epithelial, stromal and neuronal cell interactions. These interactions result to the release of various growth factors that play prominent roles during corneal wound healing response. Bone morphogenetic proteins (BMPs) are unique multi-functional potent growth factors of the transforming growth factor-beta (TGF-β) superfamily. Treatment of corneal epithelial cells with substance P and nerve growth factor resulted to an increase in the expression of BMP7 mRNA. Since BMP7 is known to modulate the process of corneal wound healing, in this present study, we investigated the influence of exogenous rhBMP7 on human corneal epithelial cell and stromal cell (SFs) function. To obtain a high-fidelity expression profiling of activated biomarkers and pathways, transcriptome-wide gene-level expression profiling of epithelial cells in the presence of BMP7 was performed. Gene ontology analysis shows BMP7 stimulation activated TGF-β signaling and cell cycle pathways, whereas biological processes related to cell cycle, microtubule and intermediate filament cytoskeleton organization were significantly impacted in corneal epithelial cells. Scratch wound healing assay showed increased motility and migration of BMP7 treated epithelial cells. BMP7 stimulation studies show activation of MAPK cascade proteins in epithelial cells and SFs. Similarly, a difference in the expression of claudin, Zink finger E-box-binding homeobox 1 was observed along with phosphorylation levels of cofilin in epithelial cells. Stimulation of SFs with BMP7 activated them with increased expression of α-smooth muscle actin. In addition, an elevated phosphorylation of epidermal growth factor receptor following BMP7 stimulation was also observed both in corneal epithelial cells and SFs. Based on our transcriptome analysis data on epithelial cells and the results obtained in SFs, we conclude that BMP7 contributes to epithelial-to-mesenchymal transition-like responses and plays a role equivalent to TGF-β in the course of corneal wound healing.
Highlights
In the cornea, endogenously produced growth factors play a crucial role in modulating the functions of corneal epithelial and stromal cells [1,2,3]
After 24 h of treatment with Substance P (SP), showed 6.2-fold increase in the expression of BMP7 mRNA whereas treatment with Nerve Growth Factor (NGF) resulted to 3.8-fold increased expression compared to the control untreated cells (Figure 1)
Since treatment of SP and NGF enhanced the expression levels of BMP7 mRNA, we studied the consequences of BMP7 on epithelial cell function by performing Gene Expression Profiling (GEP) of BMP7 stimulated epithelial cells
Summary
Endogenously produced growth factors play a crucial role in modulating the functions of corneal epithelial and stromal cells [1,2,3]. A multitude of growth factors including epidermal growth factor (EGF), transforming growth factor-alpha and beta (TGF-α and -β), keratinocyte growth factor, fibroblast growth factor, hepatocyte growth factor, insulin-like growth factor, platelet-derived growth factor along with inflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α play important roles by influencing the migration, mitosis, proliferation and differentiation of corneal cells [4,5]. BMPs are extensively expressed in the course of mammalian development and exert effect on numerous cellular functions with a wide range of biological activities on various cell types including development, morphogenesis, proliferation and extracellular matrix synthesis [17]. BMPs, by inducing the expression of extracellular matrix components, facilitate migration of cells during wound healing [24]
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